GARDASIL Merck Sharp & Dhome

Transcription

1 GARDASIL Merck Sharp & Dhome 1. INDICATIONS AND USAGE 1.1 Girls and Women GARDASIL 1 is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine: Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18 Genital warts (condyloma acuminata) caused by HPV types 6 and 11 And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18: Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS) Cervical intraepithelial neoplasia (CIN) grade 1 Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade Boys and Men GARDASIL is indicated in boys and men 9 through 26 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and Limitations of GARDASIL Use and Effectiveness The health care provider should inform the patient, parent, or guardian that vaccination does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical cancer screening per standard of care. [See Patient Counseling Information (17.1).] GARDASIL has not been demonstrated to provide protection against disease from vaccine and nonvaccine HPV types to which a person has previously been exposed through sexual activity. [See Clinical Studies (14.3, 14.4).] GARDASIL is not intended to be used for treatment of active external genital lesions; cervical, vulvar, and vaginal cancers; CIN; VIN; or VaIN. GARDASIL has not been demonstrated to protect against diseases due to HPV types not contained in the vaccine. [See Clinical Studies (14.5).] Not all vulvar and vaginal cancers are caused by HPV, and GARDASIL protects only against those vulvar and vaginal cancers caused by HPV 16 and 18. GARDASIL does not protect against genital diseases not caused by HPV. Vaccination with GARDASIL may not result in protection in all vaccine recipients. 2. DOSAGE AND ADMINISTRATION 2.1 Dosage GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2 months, 6 months. [See Clinical Studies (14.7).] 2.2 Method of Administration For intramuscular use only. Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL should not be diluted or mixed with other vaccines. After thorough agitation, GARDASIL is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored. GARDASIL should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. Syncope has been reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).] Single-Dose Vial Use Withdraw the 0.5-mL dose of vaccine from the sin-

2 GARDASIL - p.2/21 gle-dose vial using a sterile needle and syringe and use promptly. Prefilled Syringe Use With and Without Needle Guard (Safety) Device Prefilled Syringe With Needle Guard (Safety) Device Instructions for using the prefilled single-dose syringes preassembled with needle guard (safety) device NOTE: Please use the enclosed needle for administration. If a different needle is chosen, it should fit securely on the syringe and be no longer than 1 inch to ensure proper functioning of the needle guard device. Two detachable labels are provided which can be removed after the needle is guarded. At any of the following steps, avoid contact with the Trigger Fingers to keep from activating the safety device prematurely. Remove Syringe Tip Cap and Needle Cap. Attach Luer Needle by pressing both Anti-Rotation Tabs to secure syringe and by twisting the Luer Needle in a clockwise direction until secured to the syringe. Remove Needle Sheath. Administer injection per standard protocol as stated above under DOSAGE AND ADMINISTRATION. Depress the Plunger while grasping the Finger Flange until the entire dose has been given. The Needle Guard Device will NOT activate to cover and protect the needle unless the ENTIRE dose has been given. While the Plunger is still depressed, remove needle from the vaccine recipient. Slowly release the Plunger and allow syringe to move up until the entire needle is guarded. For documentation of vaccination, remove detachable labels by pulling slowly on them. Dispose in approved sharps container. Prefilled Syringe Without Needle Guard (Safety) Device This package does not contain a needle guard (safety device) or a needle. Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol. 3. DOSAGE FORMS AND STRENGTHS GARDASIL is a suspension for intramuscular administration available in 0.5-mL single dose vials and prefilled syringes. See Description (11) for the complete listing of ingredients. 4. CONTRAINDICATIONS Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL. [See Description (11).] 5. WARNINGS AND PRECAUTIONS 5.1 Syncope Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with GARDASIL. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. 5.2 Managing Allergic Reactions Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following the administration of GARDASIL. 6. ADVERSE REACTIONS Overall Summary of Adverse Reactions Headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after administration with GARDASIL. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been

3 GARDASIL - p.3/21 reported following vaccination with GARDASIL and may result in falling with injury; observation for 15 minutes after administration is recommended. [See Warnings and Precautions (5.1).] Anaphylaxis has been reported following vaccination with GARDASIL. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. Studies in Girls, Women, Boys, and Men 9 Through 26 Years of Age In 6 clinical trials (4 Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS]-controlled, 1 saline placebo-controlled, and 1 uncontrolled), 14,273 individuals were administered GARDASIL or AAHS control or saline placebo on the day of enrollment, and approximately 2 and 6 months thereafter, and safety was evaluated using vaccination report cards (VRC)-aided surveillance for 14 days after each injection of GARDASIL or AAHS control or saline placebo in these individuals. The individuals who were monitored using VRC-aided surveillance included 8180 individuals 9 through 26 years of age at enrollment who received GARDASIL and 6093 individuals who received AAHS control or saline placebo. Few individuals (0.2%) discontinued due to adverse reactions. The race distribution of the girls and women in the safety population was as follows: 62.3% White; 17.6% Hispanic (Black and White); 6.8% Asian; 6.7% Other; 6.4% Black; and % American Indian. The race distribution of the boys and men in the safety population was as follows: 42.0% White; 19.7% Hispanic (Black and White); 11.0% Asian; 11.2% Other; 15.9% Black; and 0.1% American Indian. Common Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age The injection site adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 1. Table 1. Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age* Adverse Reaction (1 to 5 Days Postvaccination) GARDASIL (N = 5088) % AAHS Control** (N = 3470)% Saline Placebo (N = 320)% Injection Site Pain Swelling Erythema Pruritus Bruising * The injection-site adverse reactions that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. ** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Common Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age The injection site adverse reactions that were observed among recipients of GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients are shown in Table 2. Table 2. Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age* Adverse Reaction (1 to 5 Days Postvaccination) GARDASIL (N = 3092) % AAHS Control** (N = 2029)% Saline Placebo (N = 274)% Injection Site Pain Erythema Swelling * The injection-site adverse reactions that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among AAHS control or saline placebo recipients. ** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Evaluation of Injection-Site Adverse Reactions by Dose in Girls and Women 9 Through 26 Years of Age An analysis of injection-site adverse reactions in girls and women by dose is shown in Table 3. Of those girls and women who reported an injectionsite reaction, 94.3% judged their injection-site adverse reaction to be mild or moderate in intensity.

4 GARDASIL - p.4/21 Table 3. Postdose Evaluation of Injection-Site Adverse Reactions in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination) GARDASIL (% occurrence) AAHS Control* (% occurrence) Saline Placebo (% occurrence) Adverse Postdose 1 Postdose 2 Postdose 3 Postdose 1 Postdose 2 Postdose 3 Postdose 1 Postdose 2 Postdose 3 Reaction N**= 5011 N = 4924 N = 4818 N = 3410 N = 3351 N = 3295 N = 315 N = 301 N = 300 Pain Mild/Moderate Severe Swelling*** Mild/Moderate Severe Erythema*** Mild/Moderate Severe * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate ** N = Number of individuals with follow-up *** Intensity of swelling and erythema was measured by size (inches): Mild = 0 to 1; Moderate = >1 to 2; Severe = >2. Adverse Reaction Table 4. Postdose Evaluation of Injection-Site Adverse Reactions in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination) GARDASIL (% occurrence) AAHS Control* (% occurrence) Saline Placebo (% occurrence) Postdose Postdose Postdose Postdose Postdose Postdose Postdose Postdose N**= 3002 N = 2897 N = 2825 N = 1950 N = 1853 N = 1799 N = 269 N = 263 Pain Mild/Moderate Severe Swelling*** Mild/Moderate Severe Erythema*** Mild/Moderate Severe * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate ** N = Number of individuals with follow-up *** Intensity of swelling and erythema was measured by size (inches): Mild = 0 to 1; Moderate = >1 to 2; Severe = > Postdose 3 N = See Table 3. Evaluation of Injection-Site Adverse Reactions by Dose in Boys and Men 9 Through 26 Years of Age An analysis of injection-site adverse reactions in boys and men by dose is shown in Table 4. Of those boys and men who reported an injection-site reaction, 96.4% judged their injection-site adverse reaction to be mild or moderate in intensity. See Table 4. Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age Headache was the most commonly reported sys- temic adverse reaction in both treatment groups (GARDASIL = 28.2% and AAHS control or saline placebo = 28.4%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 13.0% and AAHS control or saline placebo = 11.2%). Adverse reactions that were observed among recipients of GARDASIL, at a frequency of greater than or equal to 1.0% where the incidence in the GARDASIL group was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 5.

5 GARDASIL - p.5/21 Table 5. Common Systemic Adverse Reactions in Girls and Women 9 Through 26 Years of Age (GARDASIL Control)* Adverse Reactions (1 to 15 Days Postvaccination) Pyrexia Nausea Dizziness Diarrhea Vomiting Cough Toothache Upper respiratory tract infection Malaise Arthralgia Insomnia Nasal congestion GARDASIL (N = 5088) % AAHS control** or Saline Placebo (N = 3790) % * The adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. ** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age Headache was the most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 12.3% and AAHS control or saline placebo = 11.2%). Fever was the next most commonly reported systemic adverse reaction in both treatment groups (GARDASIL = 8.2% and AAHS control or saline placebo = 6.5%). Adverse reactions that were observed among recipi- ents of GARDASIL, at a frequency of greater than or equal to 1.0% where the incidence in the group that received GARDASIL was greater than or equal to the incidence in the AAHS control or saline placebo group, are shown in Table 6. Table 6. Common Systemic Adverse Reactions in Boys and Men 9 Through 26 Years of Age (GARDASIL Control)* Adverse Reactions (1 to 15 Days Postvaccination) Headache Pyrexia Pharyngolaryngeal pain Diarrhea Nasopharyngitis Nausea Upper respiratory tract infection Abdominal pain upper Myalgia Dizziness Vomiting GARDASIL (N = 3092) % AAHS control** or Saline Placebo (N = 2303) % * The adverse reactions in this table are those that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than or equal to those observed among AAHS control or saline placebo recipients. ** AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Evaluation of Fever by Dose in Girls and Women 9 Through 26 Years of Age An analysis of fever in girls and women by dose is shown in Table 7. Evaluation of Fever by Dose in Boys and Men 9 Table 7. Postdose Evaluation of Fever in Girls and Women 9 Through 26 Years of Age (1 to 5 Days Postvaccination) GARDASIL (% occurrence) AAHS Control* or Saline Placebo (% occurrence) Temperature ( F) Postdose 1 N** = 4945 Postdose 2 N = 4804 Postdose 3 N = 4671 Postdose 1 N = 3681 Postdose 2 N = 3564 Postdose 3 N = to < * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate ** N = Number of individuals with follow-up Table 8. Postdose Evaluation of Fever in Boys and Men 9 Through 26 Years of Age (1 to 5 Days Postvaccination) GARDASIL (% occurrence) AAHS Control* or Saline Placebo (% occurrence) Temperature ( F) Postdose 1 N** = 2971 Postdose 2 N = 2847 Postdose 3 N = 2791 Postdose 1 N = 2194 Postdose 2 N = 2079 Postdose 3 N = to < *AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate **N = Number of individuals with follow-up

6 GARDASIL - p.6/21 Through 26 Years of Age An analysis of fever in boys and men by dose is shown in Table 8. Serious Adverse Reactions in the Entire Study Population Across the clinical studies, 255 individuals (GARDASIL N = 126 or 0.8%; Placebo N = 129 or 1.0%) out of 29,323 (GARDASIL N = 15,706; AAHS control N = 13,023; or saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men) reported a serious systemic adverse reaction. Of the entire study population (29,323 individuals), 4% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4 cases or greater with either GARDASIL, AAHS control, saline placebo, or the total of all three) reported serious systemic adverse reactions, regardless of causality, were: - Headache [2% GARDASIL (3 cases) vs. 2% AAHS Control (2 cases)], - Gastroenteritis [2% GARDASIL (3 cases) vs. 2% AAHS Control (2 cases)], - Appendicitis [3% GARDASIL (5 cases) vs. 1% AAHS Control (1 case)], - Pelvic inflammatory disease [2% GARDASIL (3 cases) vs. 3% AAHS Control (4 cases)], - Urinary tract infection [1% GARDASIL (2 cases) vs. 2% AAHS Control (2 cases)], - Pneumonia [1% GARDASIL (2 cases) vs. 2% AAHS Control (2 cases)], - Pyelonephritis [1% GARDASIL (2 cases) vs. 2% AAHS Control (3 cases)], - Pulmonary embolism [1% GARDASIL (2 cases) vs. 2% AAHS Control (2 cases)]. - One case (06% GARDASIL; % AAHS Control or Saline Placebo) of bronchospasm; and 2 cases (1% GARDASIL; % AAHS Control or Saline Placebo) of asthma were reported as serious systemic adverse reactions that occurred following any vaccination visit. In addition, there was 1 individual in the clinical trials, in the group that received GARDASIL, who reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement impairment). Deaths in the Entire Study Population Across the clinical studies, 37 deaths (GARDASIL N = 18 or 0.1%; Placebo N = 19 or 0.1%) were reported in 29,323 (GARDASIL N = 15,706; AAHS Control N = 13,023, saline placebo N = 594) individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The events reported were consistent with events expected in healthy adolescent and adult populations. The most common cause of death was motor vehicle accident (5 individuals who received GARDASIL and 4 individuals who received AAHS Control), followed by drug overdose/suicide (2 individuals who received GARDASIL and 6 individuals who received AAHS Control), gun shot wound (1 individual who received GARDASIL and 3 individuals who received AAHS Control), and pulmonary embolus/deep vein thrombosis (1 individual who received GARDASIL and 1 individual who received AAHS Control). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal failure, 1 case of traumatic brain injury/cardiac arrest, and 1 case of systemic lupus erythematosus in the group that received GARDASIL; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical poisoning, and 1 case of myocardial ischemia in the AAHS Control group; and 1 case of medulloblastoma in the saline placebo group. Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline placebo are shown in Table 9. This population includes all girls and women who received at least

7 GARDASIL - p.7/21 Safety in Concomitant Use with RECOMBIVAX HB in Girls and Women 9 Through 26 Years of Age The safety of GARDASIL when administered conone dose of GARDASIL or AAHS control or saline placebo, and had safety data available. Table 9. Summary of Girls and Women 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL, Regardless of Causality Conditions Arthralgia/Arthritis/Arthropathy** Autoimmune Thyroiditis Celiac Disease Diabetes Mellitus Insulin-dependent Erythema Nodosum Hyperthyroidism*** Hypothyroidism Inflammatory Bowel Disease Multiple Sclerosis Nephritis Optic Neuritis Pigmentation Disorder Psoriasis# Raynaud s Phenomenon Rheumatoid Arthritis Scleroderma/Morphea Stevens-Johnson Syndrome Systemic Lupus Erythematosus Uveitis All Conditions GARDASIL (N = 10,706) n (%) 120 (1.1) 4 () 10 (0.1) 2 () 2 () 27 () 35 () 7 (0.1) 2 () 2 () 2 () 4 () 13 (0.1) 3 () 6 (0.1) 2 () 1 () 1 () 3 () 245 (2.3) AAHS Control* or Saline Placebo (N = 9412) n (%) 98 (1.0) 1 () 6 (0.1) 2 () 4 () 21 (0.2) 38 (0.4) 10 (0.1) 4 () 5 (0.1) 0 () 3 () 15 (0.2) 4 () 2 () 1 () 0 () 3 () 1 () 218 (2.3) * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate ** Arthralgia/Arthritis/Arthropathy includes the following terms: Arthralgia, Arthritis, Arthritis reactive, and Arthropathy *** Hyperthyroidism includes the following terms: Basedow s disease, Goiter, Toxic nodular goiter, and Hyperthyroidism Hypothyroidism includes the following terms: Hypothyroidism and thyroiditis Inflammatory bowel disease includes the following terms: Colitis ulcerative, Crohn s disease, and Inflammatory bowel disease Nephritis includes the following terms: Nephritis, Glomerulonephritis minimal lesion, Glomerulonephritis proliferative Pigmentation disorder includes the following terms: Pigmentation disorder, Skin depigmentation, and Vitiligo # Psoriasis includes the following terms: Psoriasis, Pustular psoriasis, and Psoriatic arthropathy Rheumatoid arthritis includes juvenile rheumatoid arthritis. One woman counted in the rheumatoid arthritis group reported rheumatoid arthritis as an adverse experience at Day 130. N = Number of individuals enrolled n = Number of individuals with specific new Medical Conditions NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories. Systemic Autoimmune Disorders in Boys and Men 9 Through 26 Years of Age In the clinical studies, 9- through 26-year-old boys and men were evaluated for new medical conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline placebo are shown in Table 10. This population includes all boys and men who received at least one dose of GARDASIL or AAHS control or saline placebo, and had safety data available. Table 10. Summary of Boys and Men 9 Through 26 Years of Age Who Reported an Incident Condition Potentially Indicative of a Systemic Autoimmune Disorder After Enrollment in Clinical Trials of GARDASIL, Regardless of Causality Conditions Alopecia Areata Ankylosing Spondylitis Arthralgia/Arthritis/ Reactive Arthritis Autoimmune Thrombocytopenia Diabetes Mellitus Type 1 Hyperthyroidism Hypothyroidism** Inflammatory Bowel Disease*** Myocarditis Proteinuria Psoriasis Vitiligo GARDASIL (N = 3092) n (%) 1 () 1 () 30 (1.0) 1 () 3 (0.1) 0 () 3 (0.1) 0 () 1 () 1 () 0 () 2 (0.1) AAHS Control* or Saline Placebo (N = 2303) n (%) 0 () 2 (0.1) 17 (0.7) 0 () 2 (0.1) 1 () 0 () 2 (0.1) 1 () 0 () 2 (0.1) 5 (0.2) All Conditions 43 (1.4) 32 (1.4) * AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate ** Hypothyroidism includes the following terms: Hypothyroidism and Autoimmune thyroiditis *** Inflammatory bowel disease includes the following terms: Colitis ulcerative and Crohn s disease N = Number of individuals who received at least one dose of either vaccine or placebo n = Number of individuals with specific new Medical Conditions NOTE: Although an individual may have had two or more new Medical Conditions, the individual is counted only once within a category. The same individual may appear in different categories.

8 GARDASIL - p.8/21 comitantly with RECOMBIVAX HB hepatitis B vaccine (recombinant) was evaluated in an AAHScontrolled study of 1871 girls and women with a mean age of 20.4 years. The race distribution of the study individuals was as follows: 61.6% White; 23.8% Other; 11.9% Black; 1.6% Hispanic (Black and White); 0.8% Asian; and % American Indian. The rates of systemic and injection-site adverse reactions were similar among girls and women who received concomitant vaccination as compared with those who received GARDASIL or RECOMBIVAX HB hepatitis B vaccine. 6.2 Postmarketing Experience The following adverse events have been spontaneously reported during post-approval use of GARDASIL. Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure. Blood and lymphatic system disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy. Respiratory, thoracic and mediastinal disorders: Pulmonary embolus. Gastrointestinal disorders: Nausea, pancreatitis, vomiting. General disorders and administration site conditions: Asthenia, chills, death, fatigue, malaise. Immune system disorders: Autoimmune diseases, hypersensitivity reactions including anaphylactic/ anaphylactoid reactions, bronchospasm, and urticaria. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia. Nervous system disorders: Acute disseminated encephalomyelitis, dizziness, Guillain-Barré syndrome, headache, motor neuron disease, paralysis, seizures, syncope (including syncope associated with tonicclonic movements and other seizure-like activity) sometimes resulting in falling with injury, transverse myelitis. Vascular disorders: Deep venous thrombosis. 7. DRUG INTERACTIONS 7.1 Use with RECOMBIVAX HB Results from clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with RECOMBIVAX HB hepatitis B vaccine (recombinant) [see Clinical Studies (14.8)]. Coadministration of GARDASIL with other vaccines has not been studied. 7.2 Use with Hormonal Contraceptives In clinical studies, 13,293 women (GARDASIL N = 6644; AAHS control or saline placebo N = 6649) who had post-month 7 follow-up used hormonal contraceptives for a total of 17,597 person-years (65.1% of the total follow-up time in the studies). Use of hormonal contraceptives or lack of use of hormonal contraceptives among study participants did not alter immune response in the per protocol efficacy (PPE) population. 7.3 Use with Systemic Immunosuppressive Medications Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines [see Use in Specific Populations (8.6)]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: Reproduction studies have been performed in female rats at doses equivalent to the recommended human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, GARDASIL should be used during pregnancy only if clearly needed. An evaluation of the effect of GARDASIL on embryo-fetal, pre- and postweaning development was conducted using rats. One group of rats was administered GARDASIL twice prior to gestation,

9 GARDASIL - p.9/21 during the period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was administered GARDASIL during the period of organogenesis (gestation Day 6) and on lactation Day 7 only. GARDASIL was administered at 0.5 ml/rat/occasion (120 mcg total protein which is equivalent to the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. Clinical Studies in Humans In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of GARDASIL. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL were instructed to defer completion of their vaccination regimen until resolution of the pregnancy. GARDASIL is not indicated for women 27 years of age or older. However, safety data in women 16 through 45 years of age was collected, and 3620 women (GARDASIL N = 1796 vs. AAHS control or saline placebo N = 1824) reported at least 1 pregnancy each. The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were 23.3% (423/1812) in women who received GARDASIL and 24.1% (438/1820) in women who received AAHS control or saline placebo. Overall, 54 and 63 women in the group that received GARDASIL or AAHS control or saline placebo, respectively (3.0% and 3.5% of all women who reported a pregnancy in the respective vac- cination groups), experienced a serious adverse reaction during pregnancy. The most common events reported were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes), and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of pregnant women who experienced such events were comparable between the groups receiving GARDASIL and AAHS control or saline placebo. There were 40 cases of congenital anomaly in pregnancies that occurred in women who received GARDASIL and 30 cases of congenital anomaly in pregnancies that occurred in women who received AAHS control or saline placebo. Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL or AAHS control or saline placebo. For pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the group that received GARDASIL compared to 1 case of congenital anomaly in the group that received AAHS control or saline placebo. The congenital anomalies seen in pregnancies with estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days following vaccination, 35 cases of congenital anomaly were observed in the group that received GARDASIL compared with 29 cases of congenital anomaly in the group that received AAHS control or saline placebo. Pregnancy Registry for GARDASIL Merck & Co., Inc. maintains a Pregnancy Registry to monitor fetal outcomes of pregnant women exposed to GARDASIL. Patients and health care providers are encouraged to report any exposure to GARDASIL during pregnancy by calling (800)

10 GARDASIL - p.10/ Nursing Mothers Women 16 Through 26 Years of Age It is not known whether GARDASIL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GARDASIL is administered to a nursing woman. A total of 995 nursing mothers (vaccine N = 500, AAHS control N = 495) were given GARDASIL or AAHS control during the vaccination period of the clinical trials. Overall, 21 and 10 infants of women who received GARDASIL or AAHS control, respectively (representing 4.2% and 2.0% of the total number of women who were breast-feeding during the period in which they received GARDASIL or AAHS control, respectively), experienced a serious adverse reaction. In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 6) whose mothers received GARDASIL had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received AAHS control. In these studies, the rates of other adverse reactions in the mother and the nursing infant were comparable between vaccination groups. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients below 9 years of age. 8.5 Geriatric Use The safety and effectiveness of GARDASIL have not been evaluated in a geriatric population, defined as individuals aged 65 years and over. 8.6 Immunocompromised Individuals The immunologic response to GARDASIL may be diminished in immunocompromised individuals [see Drug Interactions (7.3)]. 10. OVERDOSAGE There have been reports of administration of higher than recommended doses of GARDASIL. In general, the adverse event profile reported with overdose was comparable to recommended single doses of GARDASIL. 11. DESCRIPTION GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminumcontaining adjuvant and the final purification buffer. GARDASIL is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection. The product does not contain a preservative or antibiotics. After thorough agitation, GARDASIL is a white, cloudy liquid. 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action HPV only infects human beings. Animal studies with

11 GARDASIL - p.11/21 analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility GARDASIL has not been evaluated for the potential to cause carcinogenicity or genotoxicity. GARDASIL administered to female rats at a dose of 120 mcg total protein, which is equivalent to the recommended human dose, had no effects on mating performance, fertility, or embryonic/fetal survival. The effect of GARDASIL on male fertility has been studied in male rats at an intramuscular dose of 0.5 ml/ rat/occasion (120 mcg total protein which is equivalent to the recommended human dose). One group of male rats was administered GARDASIL once, 3 days prior to cohabitation, and a second group of male rats was administered GARDASIL three times, at 6 weeks, 3 weeks, and 3 days prior to cohabitation. There were no treatment-related effects on reproductive performance including fertility, sperm count, and sperm motility. There were no treatment-related gross or histomorphologic and weight changes on the testes. 14. CLINICAL STUDIES CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts. In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer. Efficacy was assessed in 5 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Study 1, N = 2391 girls and women) and the second evaluated all components of GARDASIL (Study 2, N = 551 girls and women). Two Phase III studies evaluated GARDASIL in 5442 (Study 3) and 12,157 (Study 4) girls and women. A third Phase III study, Study 5, evaluated GARDASIL in 4055 boys and men. Together, these five studies evaluated 24,596 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 2 years and 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years). The race distribution of the girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 1% Asian; and 0.1% American Indian. The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, and 2.3 years for Study 1, Study 2, Study 3, Study 4, and Study 5, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan. Overall, 73% of 16- through 26-year-old girls and women and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR [Polymerase Chain Reaction] negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment. A total of 27% of 16- through 26-year-old girls and

12 GARDASIL - p.12/21 women and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women and 78% of 16- through 26-yearold boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types. In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints. Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naïve (PCR negative and seronegative) were counted. For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types Prophylactic Efficacy HPV Types 6, 11, 16, and 18 in Girls and Women 16 Through 26 Years of Age GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type. The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the perprotocol efficacy (PPE) population, consist- ing of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit. GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11). In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types. Table 11. Analysis of Efficacy of GARDASIL in the PPE* Population** of 16- Through 26-Year-Old Girls and Women for Vaccine HPV Types Population GARDASIL AAHS Control % Efficacy N Number of cases N Number of cases (95% CI) HPV 16- or 18-related CIN 2/3 or AIS Study 1*** (65.1, 10) Study ( , 10) Study (89.2, 10) Study (88.2, 99.6) Combined Protocols (93.5, 99.8) HPV 16-related CIN 2/3 or AIS Combined Protocols (92.3, 99.8) HPV 18-related CIN 2/3 or AIS Combined Protocols (86.6, 10) HPV 16- or 18-related VIN 2/3 Study Not calculated Study (14.4, 10)

13 GARDASIL - p.13/21 Study (-5, 10) Combined Protocols (55.5, 10) HPV 16- or 18-related VaIN 2/3 Study Not calculated Study (-10.1, 10) Study (-5, 10) Combined Protocols (49.5, 10) HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS 10 Study (-138.4, 10) Study (95.1, 10) Study (88.0, 97.2) Combined Protocols (92.3, 98.2) HPV 6-, 11-, 16-, or 18-related Genital Warts 10 Study (-139.5, 10) Study (93.5, 10) Study (94.5, 99.8) Combined Protocols (96.2, 99.9) HPV 6- and 11-related Genital Warts Combined Protocols 99.0 (96.2, 99.9) * The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7). ** See Table 13 for analysis of vaccine impact in the general population. *** Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria N = Number of individuals with at least 1 follow-up visit after Month 7 CI = Confidence Interval Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan. Note 3: Table 11 does not include cases due to non-vaccine HPV types. AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through month 60, was noted to be 100% (95% CI: 12.3%, 10%) among girls and women in the per protocol population naïve to the relevant HPV types. GARDASIL was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were naïve for those specific HPV types at baseline Prophylactic Efficacy HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of boys and men who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7). Efficacy was measured starting after the Month 7 visit. GARDASIL was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in those boys and men who were PCR negative and seronegative at baseline (Table 12). Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance. Table 12. Analysis of Efficacy of GARDASIL in the PPE Population of 16- Through 26-Year-Old Boys and Men for Vaccine HPV Types Endpoint GARDASIL AAHS Control %Efficacy (95% N* Number N* Number of cases of cases CI) External Genital Lesions HPV 6-, 11-, 16-, or 18- related External Genital Lesions (69.2, 98.1) Condyloma (65.5, 97.9) PIN 1/2/ (-141.2, 10) *N = Number of individuals with at least 1 follow-up visit after Month 7 CI = Confidence Interval AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate 14.3 Population Impact in Girls and Women 16 Through 26 Years of Age Effectiveness of GARDASIL in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Genital Disease in

14 GARDASIL - p.14/21 Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types The clinical trials included girls and women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL with respect to HPV 6-, 11-, 16-, and 18-related cervical and genital disease in these girls and women. Here, analyses included events arising among girls and women regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination. The impact of GARDASIL in girls and women regardless of current or prior exposure to a vaccine HPV type is shown in Table 13. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine s efficacy in girls and women who are naïve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in girls and women who were positive for vaccine HPV infection, as well as vaccine impact among girls and women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type detected in the group that received GARDASIL occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1. There was no clear evidence of protection from disease caused by HPV types for which girls and women were PCR positive regardless of serostatus at baseline. Table 13. Effectiveness of GARDASIL in Prevention of HPV 6, 11, 16, or 18 Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types Endpoint HPV 16- or 18 related CIN 2/3 or AIS Analysis GARDASIL or HPV 16 L1 VLP Vaccine AAHS Control % Reduction (95% CI) N Cases N Cases Prophylactic Efficacy* (93.3, 99.3) HPV 16 and/or HPV 18 Positive at Day ** --*** Girls and Women Regardless of Current or Prior Exposure to HPV (41.1, 60.7) or 18 HPV 16- or Prophylactic Efficacy* (82.4, 99.9) 18-related HPV 16 and/or HPV 18 VIN 2/3 or Positive at Day *** VaIN 2/3 Girls and Women Regardless of Current or Prior Exposure to HPV (5, or 18 HPV 6-, 11-, Prophylactic Efficacy* (91.5, 97.1) 16-, 18-related CIN (CIN or HPV 18 Positive at Day 1 HPV 6, HPV 11, HPV 16, and/ # # --*** 1, CIN 2/3) Girls and Women or AIS Regardless of Current or Prior Exposure to Vaccine HPV 6-, 11-, 16-, or 18-related Genital Warts HPV 6- or 11- related Genital Warts (54.6, 67.4) Prophylactic Efficacy* (92.6, 98.1) HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at *** Day 1 Genital Warts Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types (73.9, 85.3) Prophylactic Efficacy* (93.0, 98.4) HPV 6 and/or HPV 11 Positive at Day *** Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types (73.7, 85.2) * Includes all individuals who received at least 1 vaccination and who were naïve (PCR negative and seronegative) to HPV 6, 11, 16, and/or 18 at Day 1. Case counting started at 1 month postdose 1. ** Out of the 148 AAHS control cases of 16/18 CIN 2/3, 2 women were missing serology or PCR results for Day 1. *** There is no expected efficacy since GARDASIL has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity. Includes all individuals who received at least 1 vaccination (regardless of baseline HPV status at Day 1). Case counting started at 1 month postdose 1. Percent reduction includes the prophylactic efficacy of GARDASIL as well as the impact of GARDASIL on the course of infections present at the start of the vaccination. # Includes 2 AAHS control women with missing serology/pcr data at Day 1. Includes 1 woman with missing serology/pcr data at Day 1. CI = Confidence Interval N = Number of individuals who have at least one follow-up visit after Day 1 Note 1: The 16- and 18-related CIN 2/3 or AIS composite endpoint included data from studies 1, 2, 3, and 4. All other endpoints only included data from studies 2, 3, and 4. Note 2: Positive status at Day 1 denotes PCR positive and/or seropositive for the respective type at Day 1. Note 3: Table 13 does not include disease due to non-vaccine HPV types. AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate